U.S. patent number 5,703,244 [Application Number 08/754,641] was granted by the patent office on 1997-12-30 for process for preparation of chiral 3-amino-pyrrolidine and analogous bicyclic compounds.
This patent grant is currently assigned to Abbott Laboratories. Invention is credited to Daniel T. Chu, Lisa Anne Hasvold, Qun Li, Wei-Bo Wang.
United States Patent |
5,703,244 |
Li , et al. |
December 30, 1997 |
Process for preparation of chiral 3-amino-pyrrolidine and analogous
bicyclic compounds
Abstract
A process for the preparation of chiral 3-aminopyrrolidine and
analogous bicyclic derivatives from dihydroxy olefins by treatment
with titanium isopropoxide, an optically active tartrate ester and
tert-butyl hydroperoxide, followed by subsequent alkylation of the
intermediate with an alkyl or alkenyl magnesium halide, then
pyrrolidine ring formation by condensation with an arylmethylamine,
subsequent chiral replacement of a ring hydroxyl group with an
amino group with further protection thereof, optional additional
substitution closing of the second ring, and hydrogenolysis to
remove a ring-nitrogen protecting group.
Inventors: |
Li; Qun (Libertyville, IL),
Wang; Wei-Bo (Grayslake, IL), Chu; Daniel T. (Santa
Clara, CA), Hasvold; Lisa Anne (Grayslake, IL) |
Assignee: |
Abbott Laboratories (Abbott
Park, IL)
|
Family
ID: |
25035692 |
Appl.
No.: |
08/754,641 |
Filed: |
November 21, 1996 |
Current U.S.
Class: |
548/557 |
Current CPC
Class: |
C07D
471/04 (20130101); C07D 207/14 (20130101); C07D
455/02 (20130101); Y02P 20/55 (20151101) |
Current International
Class: |
C07D
207/00 (20060101); C07D 207/14 (20060101); C07D
471/00 (20060101); C07D 455/02 (20060101); C07D
455/00 (20060101); C07D 471/04 (20060101); C07D
207/09 () |
Field of
Search: |
;548/557 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
4990517 |
February 1991 |
Petersen et al. |
5059597 |
October 1991 |
Petersen et al. |
5140033 |
August 1992 |
Schriewer et al. |
|
Foreign Patent Documents
|
|
|
|
|
|
|
9116894 |
|
Nov 1991 |
|
WO |
|
9415939 |
|
Jul 1994 |
|
WO |
|
9510519 |
|
Apr 1995 |
|
WO |
|
Primary Examiner: McKane; Joseph
Attorney, Agent or Firm: Anand; Mona
Claims
What is claimed is:
1. A process for the preparation of chiral 3-aminopyrrolidine
compounds having the formula: ##STR25## wherein R is C.sub.1
-C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.2 -C.sub.6
-alkynyl, or C.sub.3 -C.sub.6 -cycloalkyl, and R.sup.1 is hydrogen,
C.sub.1 -C.sub.6 -alkyl or an amino-protecting group;
comprising:
(a) protecting a single hydroxyl group of selected positional
isomer of 2-butene-1,4-diol, by stepwise treatment with a base, an
arylmethyl halide and a tetraalkylammonium halide, and isolating a
monoprotected hydroxy-olefin having the formula:
wherein Ar represents the aryl moiety;
(b) chirally oxidizing the monoprotected hydroxy-olefin with
titanium isopropoxide, an optically active chiral tartrate ester
and t-butyl hydroperoxide, and isolating an epoxy compound having
the formula: ##STR26## (c) reacting the epoxy compound with an
R--Mg--X compound, wherein R is as defined above, and X is halogen,
under Grignard Reaction conditions, and isolating the chiral third
intermediate compound having the formula: ##STR27## (d) removing
the protecting group from the chiral third intermediate compound,
and isolating the chiral fourth intermediate compound having the
formula: ##STR28## (e) sulfonylating the chiral fourth intermediate
compound by treatment with a substituted sulfonyl chloride, and
isolating the chiral diprotected triol compound having the formula:
##STR29## wherein L represents the substituted sulfonyl moiety; (f)
cyclizing the chiral diprotected triol compound by treatment with
an arylmethylamine compound, and isolating the chiral pyrrolidine
intermediate having the formula: ##STR30## (g) replacing the
hydroxyl group of the chiral pyrrolidine intermediate with an amino
group by an amination reaction that inverts the chiral center, and
isolating the chiral aminopyrrolidine compound having the formula:
##STR31## (h) derivatizing the amino group of the chiral
aminopyrrolidine compound, and isolating the chiral
substituted-aminopyrrolidine compound having the formula: ##STR32##
wherein R.sup.1 is as defined above; (i) deprotecting the ring
nitrogen of the chiral substituted-aminopyrrolidine compound, and
isolating the desired product.
2. A process according to claim 1 wherein in step (a) the
2-butene-1,4-diol is the cis isomer; in step (b), the optically
active chiral tartrate ester is D-(-)-diisopropyl tartrate; and the
product has the cis-3S,4S-configuration.
3. A process according to claim 1 wherein in step (a) the
2-butene-1,4-diol is the cis isomer; in step (b), the optically
active chiral tartrate ester is L-(+)-diisopropyl tartrate; and the
product has the cis-3R,4R-configuration.
4. A process according to claim 1 wherein in step (a) the
2-butene-1,4-diol is the trans-isomer; in step (b), the optically
active chiral tartrate ester is D-(-)-diiso-propyl tartrate; and
the product has the trans-3R,4S-configuration.
5. A process according to claim 1 wherein in step (a) the
2-butene-1,4-diol is the trans isomer; in step (b), the optically
active chiral tartrate ester is L-(+)-diisopropyl tartrate; and the
product has the trans-3S ,4R-configuration.
6. A process according to claim 1, wherein R.sup.1 is
t-butyloxycarbonyl and in step (a) the 2-butene-1,4-diol is treated
with one equivalent of NaH in an aprotic polar organic solvent at
from -20.degree. C. to 5.degree. C. under an inert atmosphere and
anhydrous conditions, and the arylmethyl halide of the subsequent
reaction, performed at ambient temperature for 8 to 24 hours, is
selected from the group consisting of benzyl bromide, benzyl
chloride, benzyl iodide, 4-bromobenzyl bromide, and 4-chlorobenzyl
bromide; in step (b), the first intermediate compound is reacted
with titanium isopropoxide, an optically active chiral tartrate
ester and tert-butyl hydroperoxide in dry methylene chloride in the
presence of 4 .ANG. molecular sieves at -40.degree. C. to
-20.degree. C. for 0.5 to 24 hours; in step (c) the Grignard
reaction is performed with a CuCN catalyst at -78.degree. to
-20.degree. C., followed by treatment of the intermediate with
NaIO.sub.4 at ambient temperature in aqueous THF; in step (d) the
protecting group is removed from the chiral third intermediate
compound by hydrogenolysis over Pd/C in an alcoholic solution; in
step (e) the fourth intermediate compound (5) is sulfonylated with
methanesulfonyl chloride; in step (f) the chiral diprotected triol
compound (6) is cyclized with benzylamine in an alcoholic solution
and in the presence of a base at 80.degree. C.-120.degree. C.; in
step (g) the hydroxyl group of the chiral pyrrolidine intermediate
is replaced by treatment with triphenylphosphine,
diethylazodicarboxylate, and phthalylamine, followed by treatment
with hydrazine in ethanol; in step (h), the seventh intermediate
compound is derivatized by treatment with di-t-butyldicarbonate;
and in step (i), the ring nitrogen of the chiral
substituted-aminopyrrolidine compound is deprotected by
hydrogenolysis over Pd/C in an alcoholic solution.
7. A process according to claim 6 wherein R is C.sub.1 -C.sub.6
-alkyl.
8. A process according to claim 7 wherein R is ethyl.
Description
TECHNICAL FIELD
The present invention relates to a process for the preparation of
chiral 3-amino-pyrrolidine derivatives which have use as
intermediates in the preparation of certain pyrido[1,2-a]pyrimidine
and quinolone antibacterial agents.
BACKGROUND OF THE INVENTION
The therapeutic use of certain pyrido[1,2-a]pyrimidine derivatives
as antibacterial agents has been described in PCT patent
applications WO 9116894, published Nov. 14, 1991, and WO 9510519,
published Apr. 20, 1995. Quinolone antibacterial agents are well
known and are described, for example, in U.S. Pat. Nos. 4,990,517;
5,140,033; 5,059,597; and PCT application WO 9415938.
More efficient processes for the preparation of key chiral
intermediates for use in the synthesis of antibiotic agents are
needed to ensure the ready availability of the compounds.
SUMMARY OF THE INVENTION
The present invention describes an efficient process for the
enantioselective preparation of chiral 3-aminopyrrolidine,
2,7-diaza-bicyclo[3.3.0]octane, 2,8-diaza-bicyclo[4.3.0]nonane and
2,9-diaza-bicyclo[5.3.0]decane derivatives which have use as
intermediates in the preparation of certain pyrido[1,2-a]pyrimidine
and quinolone antibacterial agents.
In one aspect, the present invention relates to a process for the
preparation of chiral 3-aminopyrrolidine compounds having the
formula: ##STR1## wherein R is C.sub.1 -C.sub.6 -alkyl, C.sub.2
-C.sub.6 -alkenyl, C.sub.2 -C.sub.6 -alkynyl, or C.sub.3 -C.sub.6
-cycloalkyl, and R.sup.1 is hydrogen, C.sub.1 -C.sub.6 -alkyl or an
amino-protecting group; the method comprising:
(a) protecting a single hydroxyl group of selected positional
isomer of 2-butene-1,4-diol, by stepwise treatment with a base, an
arylmethyl halide and a tetraalkyl-ammonium halide, and isolating a
monoprotected hydroxy-olefin having the formula:
wherein Ar represents the aryl moiety;
(b) chirally oxidizing the monoprotected hydroxy-olefin with
titanium isopropoxide, an optically active chiral tartrate ester
and t-butyl hydroperoxide, and isolating an epoxy compound having
the formula: ##STR2##
(c) reacting the epoxy compound with an R--Mg--X compound, wherein
R is as defined above, and X is halogen, under Grignard Reaction
conditions, and isolating the chiral third intermediate compound
having the formula: ##STR3##
(d) removing the protecting group from the chiral third
intermediate compound, and isolating the chiral fourth intermediate
compound having the formula: ##STR4##
(e) sulfonylating the chiral fourth intermediate compound by
treatment with a substituted sulfonyl chloride, and isolating the
chiral diprotected triol compound having the formula: ##STR5##
wherein L represents the substituted sulfonyl moiety;
(f) cyclizing the chiral diprotected triol compound by treatment
with an arylmethylamine compound, as defined below, and isolating
the chiral pyrrolidine intermediate having the formula:
##STR6##
(g) replacing the hydroxyl group of the chiral pyrrolidine
intermediate with an amino group by an amination reaction that
inverts the chiral center, and isolating the chiral
aminopyrrolidine compound having the formula: ##STR7##
(h) derivatizing the amino group of the chiral aminopyrrolidine
compound, and isolating the chiral substituted-aminopyrrolidine
compound having the formula: ##STR8## wherein R.sup.1 is as defined
above;
(i) deprotecting the ring nitrogen of the chiral
substituted-aminopyrrolidine compound, and isolating the desired
product.
In another aspect, the present invention relates to a process for
the preparation of chiral compounds having the formula: ##STR9##
wherein n is 0, 1 or 2, and R.sup.1 is hydrogen, C.sub.1 -C.sub.6
-alkyl or an amino-protecting group;
(a) protecting a single hydroxyl group of selected positional
isomer of 2-butene-1,4-diol, by stepwise treatment with a base, an
arylmethyl halide, and a tetraalkylammonium halide, and isolating a
monoprotected hydroxy-olefin having the formula:
wherein Ar represents the aryl moiety;
(b) chirally oxidizing the monoprotected hydroxy-olefin with
titanium isopropoxide, an optically active chiral tartrate ester
and t-butyl hydroperoxide, and isolating an epoxy compound having
the formula ##STR10##
(c) reacting the epoxy compound with an R.sup.2 --Mg--X compound,
wherein R.sup.2 is vinyl, allyl or 3-butenyl, and X is halogen,
under Grignard Reaction conditions, and isolating the chiral third
intermediate compound having the formula: ##STR11##
(d) removing the protecting group from the chiral third
intermediate compound, and isolating the chiral fourth intermediate
compound having the formula: ##STR12##
(e) sulfonylating the chiral fourth intermediate compound by
treatment with a substituted sulfonyl chloride, and isolating the
chiral diprotected triol compound having the formula: ##STR13##
wherein L represents the substituted sulfonyl moiety;
(f) cyclizing the chiral diprotected triol compound by treatment
with an arylmethylamine compound, and isolating the chiral
pyrrolidine intermediate having the formula: ##STR14##
(g) replacing the hydroxyl group of the chiral pyrrolidine
intermediate with an amino group by an amination reaction that
inverts the chiral center, and isolating the chiral
aminopyrrolidine compound having the formula: ##STR15##
(h) derivatizing the amino group of the chiral aminopyrrolidine
compound, and isolating the chiral substituted-aminopyrrolidine
compound having the formula: ##STR16## wherein R.sup.1 is as
defined above;
(i) oxidizing the chiral substituted-aminopyrrolidine compound with
a hydroboration reagent, and isolating the chiral hydroxyalkyl
compound having the formula: ##STR17##
(j) reacting the chiral hydroxyalkyl compound with
triphenylphosphine and diethylazobicarboxylate under Mitsunobu
Reaction conditions in an aprotic solvent to obtain the compound
having the formula: ##STR18##
(k) deprotecting the ring nitrogen of the chiral bicyclic compound,
and isolating the desired product.
The instant process for preparing these chiral intermediates from
dihydroxy olefin compounds is more economical and more practical
for large scale synthesis than the process for preparation of
certain chiral 3-aminopyrrolidine derivatives described in PCT
patent applications WO 9116894 (published Nov. 14, 1991) and WO
9510519 (published Apr. 20, 1995). One distinct advantage of the
process of the invention over the published methods is that no
large scale chiral chromatographic purifications are required.
DETAILED DESCRIPTION OF THE INVENTION
The term "C.sub.1 -C.sub.6 -alkyl" refers to saturated, straight-
or branched-chain hydrocarbon radicals containing between one and
six carbon atoms including, but not limited to, methyl, ethyl,
propyl, i-propyl, n-butyl, tert-butyl, pentyl, neopentyl and
hexyl.
The term "C.sub.2 -C.sub.6 -alkenyl", as used herein, refers to
mono-unsaturated straight- or branched-chain hydrocarbon radicals
containing from two to six carbon atoms including, but not limited
to, vinyl, propenyl, n-butenyl, i-butenyl, n-pentenyl, and
n-hexenyl.
The term "C.sub.2 -C.sub.6 -alkynyl", as used herein, refers to
straight- or branched-chain hydrocarbon radicals possessing a
single triple bond and containing from two to six carbon atoms
including, but not limited to, ethynyl, propynyl, n-butynyl,
n-pentynyl, and n-hexynyl.
The term "amino-protecting group", as used herein, refers to an
easily removable group which is known in the art to protect an
amino group against undesirable reaction during synthetic
procedures and to be selectively removable. The use of
amino-protecting groups is well known in the art for protecting
groups against undesirable reactions during a synthetic procedure
and many such protecting groups are known, cf, for example, T. H.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
2nd edition, John Wiley & Sons, New York (1991). Examples of
amino-protecting groups include, but are not limited to, acyl
groups, including acetyl, trifluoroacetyl, benzoyl and the like;
acyloxy groups, including t-butyloxycarbonyl (BOC) and
carbobenzyloxy, and the like.
The term "aprotic solvent" as used herein refers to a solvent that
is relatively inert to proton activity, i.e., not acting as a
proton-donor. Examples include, but are not limited to,
hydrocarbons, such as hexane and toluene, for example, halogenated
hydrocarbons, such as, for example, methylene chloride, ethylene
chloride, chloroform, and the like, heterocyclic compounds, such
as, for example, tetrahydrofuran and N-methylpyrrolidinone, and
ethers such as diethyl ether, bis-methoxymethyl ether. Such
compounds are well known to those skilled in the art, and it will
be obvious to those skilled in the art that individual solvents or
mixtures thereof may be preferred for specific compounds and
reaction conditions, depending upon such factors as the solubility
of reagents, reactivity of reagents and preferred temperature
ranges, for example. Further discussions of aprotic solvents may be
found in organic chemistry textbooks or in specialized monographs,
for example: Organic Solvents Physical Properties and Methods of
Purification, 4th ed., edited by John A. Riddick, et al., Vol. II,
in the Techniques of Chemistry Series, John Wiley & Sons, NY,
1986.
The term "arylmethyl halide", as used herein, refers to a
substituted or unsubstituted benzyl halide compound, including, but
not limited to, benzyl bromide, benzyl chloride, benzyl iodide,
4-bromobenzyl bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl
bromide, and the like.
The term "C.sub.3 -C.sub.6 -cycloalkyl", as used herein, refers to
saturated cyclic hydrocarbon radicals containing from three to six
carbon atoms. Illustrative of C.sub.3 -C.sub.6 -cycloalkyl groups
are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term "halogen", as used herein, refers to chlorine, bromine,
fluorine and iodine.
The term "optically active chiral tartrate ester", as used herein,
refers to esters of D-(-)-tartaric or L-(+)-tartaric acid, such as
for example, D-(-)-dimethyl tartrate, D-(-)-diethyl tartrate,
D-(-)-diisopropyl tartrate, L-(+)-dimethyl tartrate, L-(+)-diethyl
tartrate, L-(+)-diisopropyl tartrate, or the like.
The term "substituted sulfonyl chloride compound", refers to an
alkyl or aryl substituted sulfonyl chloride, including, but not
limited to, methanesulfonyl chloride, p-toluenesulfonyl chloride,
benzenesulfonyl chloride and the like.
The term "tetraalkylammonium halide", as used herein, refers to the
halide salts, such as chloride, fluoride, or bromide salts, of
quaternary alkylammonium compounds wherein the alkyl moieties are
selected from C.sub.1 -C.sub.6 -alkyl, as defined above, such as
for example, tetramethylammonium chloride, tetrabutylammonium
fluoride, tetraethylammonium bromide, tetrapropylammonium iodide,
tetrapentylammonium chloride, tetrahexylammonium chloride, and the
like.
Abbreviations which have been used in the descriptions of the
schemes and the examples that follow are: BOC for
t-butyloxycarbonyl; DEAD for diethylazodicarboxylate; DMF for
dimethylformamide; DPPA for diphenylphosphoryl azide; LDA for
lithium diisopropylamide; Me.sub.2 S for dimethyl sulfide;
PPh.sub.3 for triphenylphosphine; THF for tetrahydrofuran.
The process of the invention for preparing 3-aminopyrrolidine
derivatives may be applied selectively to prepare a specific chiral
cis- or trans-isomer of the 3-aminopyrrolidine compounds.
Chiral cis-3-aminopyrrolidine derivatives may be obtained by the
use of the cis-isomer of 2-butene-1,4-diol in step (a). The chiral
cis-3-aminopyrrolidine having either the 3S,4S- or the
3R,4R-configuration may be obtained by varying the optically active
tartrate ester referred to in step (b). Specifically, when the
oxidation is performed with the assistance of the D-(-)-tartrate
ester, the 3S,4S-product is obtained. Conversely, when the
oxidation is performed with the assistance of the L-(+)-tartrate
ester, the 3R,4R-product is obtained.
Chiral trans-3-aminopyrrolidine derivatives may be obtained by the
use of the trans-isomer of 2-butene-1,4-diol in step (a) of the
process. The specific chiral trans-3-aminopyrrolidine having either
the 3S,4R- or the 3R,4S-configuration may subsequently be obtained
by varying the optically active tartrate ester referred to in step
(b) of the process. Specifically, when the oxidation is performed
with the assistance of the L-(+)-tartrate ester, the 3S,4R-product
is obtained. Conversely, when the oxidation is performed with the
assistance of the D-(-)-tartrate ester, the 3R,4S-product is
obtained.
The present process utilizes the Sharpless reaction (e.g., K. B.
Sharpless, et at., J. Org. Chem., 51:1922-1925 (1986) and J. Amer.
Chem. Soc., 102:5974-5976, (1980)) to perform chiral oxidation of
olefins, with subsequent manipulation of the chiral oxidation
products and conversion into the desired chiral antibacterial
intermediates.
The process of the invention for obtaining specific chiral cis- and
trans-isomers of the desired 3-aminopyrrolidine compounds may be
better understood by reference to the reaction Schemes 1 and 2
illustrated below. ##STR19##
One embodiment of the process of the invention is illustrated in
Scheme 1, which describes the manner in which the process may be
utilized for preparing the cis-isomers of substituted chiral
3-aminopyrrolidines. A cis-2-butenediol (1) is treated with 1
equivalent of a base, followed by treatment with an arylmethyl
halide and a tetraalkylammonium halide to prepare the
mono-protected compound (2), wherein Ar represents the aryl moiety.
Suitable bases include NaH, K.sub.2 CO.sub.3, n-butyllithium,
lithium bis(trimethylsilylamide), and the like. Illustrative
examples of arylmethyl halides include, but are not limited to,
benzyl bromide, benzyl chloride, benzyl iodide, 4-bromobenzyl
bromide, 4-chlorobenzyl bromide, 4-methoxybenzyl bromide, and the
like. The reaction is carried out most easily under an inert
atmosphere and anhydrous conditions in an aprotic polar organic
solvent, and at a temperature from -20.degree. C. to 25.degree. C.
for 8 to 24 hours.
Compound (2) is isolated and dried, then chirally oxidized (under
the Sharpless Reaction conditions) with titanium isopropoxide, an
optically active D-(-)-tartrate ester, for example,
D-(-)-diisopropyl tartrate or D-(-)-diethyl tartrate, and
tert-butyl hydroperoxide. The reaction is carried out most easily
under an inert atmosphere in a suitable anhydrous organic solvent,
and also in the presence of 4 .ANG. molecular sieves to remove the
water of reaction. Suitable organic solvents include methylene
chloride, chloroform, toluene, and the like. The reaction may
require stirring at -20.degree. C. to ambient temperature for 0.5
to 48 hours. The reaction is quenched with Me.sub.2 S and 10%
aqueous tartaric acid solution and stirred at room temperature. The
organic layer is separated and washed with water and brine, then
dried over MgSO.sub.4 to afford the epoxy compound (3).
Compound (3) is then reacted with an R--Mg--X compound, wherein R
is C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.2
-C.sub.6 -alkynyl, or C.sub.3 -C.sub.6 -cycloalkyl, and X is
bromine, chlorine or iodine, under Grignard Reaction conditions,
usually in the presence of a copper salt as a catalyst at
-50.degree. C. to ambient temperature. Illustrative of, but not
limited to, copper salt catalysts are CuCN, CuI, CuCl, or a
CuBr--Me.sub.2 S complex. The reaction mixture is then preferably
treated with NaIO.sub.4 or KIO.sub.4 to remove 1,2-diol by-products
in a polar organic solvent at ambient temperature. Illustrative of,
but not limited to, polar organic solvents include tetrahydrofuran,
methanol, ethanol, i-propanol, t-butanol, acetone, and the like.
The desired compound (4) is separated by chromatography, and the
arylmethyl group is then removed to give compound (5). The
arylmethyl group may be removed by treatment with sodium in liquid
ammonia or by hydrogenolysis in a polar organic solvent at ambient
temperature, preferably with the aid of a Pd catalyst, such as Pd/C
or palladium acetate.
Compound (5) is then sulfonylated by treatment with a substituted
sulfonyl chloride compound to give compound (6), wherein L
represents the substituted sulfonyl moiety. Illustrative of, but
not limited to, suitable sulfonyl chloride compounds are
methanesulfonyl chloride, p-toluenesulfonyl chloride,
benzenesulfonyl chloride, and the like.
Compound (6) is then cyclized by treating the chiral diprotected
triol compound with an arylmethylamine compound to give compound
(7), wherein Ar represents the aryl moiety. This reaction is
preferably carried out in a suitable polar organic solvent at an
elevated temperature, for example 60.degree. C. to 120.degree. C.
Illustrative of, but not limited to, appropriate arylmethylamine
compounds are benzylamine, 4-methylbenzylamine,
4-methoxybenzylamine, and the like. The reaction is preferably
performed in the presence of base to afford higher yields. Examples
of suitable bases for this reaction include, but are not limited
to, NaHCO.sub.3, Na.sub.2 CO.sub.3, KHCO.sub.3, K.sub.2 CO.sub.3,
triethylamine, pyridine, N-methylmorpholine, N-methylpiperidine,
N,N-diisopropylethylamine, and the like.
The hydroxyl group of the chiral pyrrolidine intermediate (7) is
then replaced with an amino group by an amination reaction that
inverts the chiral center to give compound (8). Suitable
replacement reaction conditions include (a) treatment of the
hydroxyl group under Mitsunobu Reaction conditions with Ph.sub.3 P,
DEAD, and phthalylamine, followed by treatment with hydrazine; (b)
treatment of the hydroxyl group under Mitsunobu Reaction conditions
with Ph.sub.3 P, DEAD, and DPPA followed by reduction of the
intermediate azide with Ph.sub.3 P and water; (c) reaction of the
hydroxyl group with a substituted sulfonyl chloride compound, for
example, methanesulfonyl chloride, p-toluenesulfonyl chloride,
benzenesulfonyl chloride, followed by replacement of the
sulfonyloxy group with an azide group by treatment with sodium or
potassium azide and reduction of the intermediate azide with
Ph.sub.3 P and water.
Compound (8) is then optionally derivatized on the amino group to
give compound (9). This may be done by treatment with an
amino-protecting group reagent, for example, an acyl chloride, an
acyloxy chloride or anhydride, and preferably
di-t-butyldicarbonate, trifluoroacetyl chloride or trifluoroacetyl
anhydride in an aprotic solvent, or by treatment with an alkyl
halide in the presence of base.
Compound (9) is then deprotected by methods known in the art to
give the desired compound (10). The arylmethyl group may be removed
by treatment with sodium in liquid ammonia or by hydrogenolysis in
a polar organic solvent at ambient temperature, preferably with the
aid of a Pd catalyst, such as Pd/C or palladium acetate.
##STR20##
Another embodiment of the process of the invention is illustrated
in Scheme 2, which describes the manner in which the process may be
utilized for preparing the trans-isomers of substituted chiral
3-aminopyrrolidines. A trans-2-butenediol (11) is treated with 1
equivalent of a base, followed by treatment with an arylmethyl
halide and a tetraalkylammonium halide as described in Scheme 1
above to prepare the mono-protected compound (12), wherein Ar
represents the aryl moiety. Compound (12) is isolated and dried,
then chirally oxidized (under the Sharpless Reaction conditions)
with titanium isopropoxide, an optically active L-(+)-tartrate
ester, for example, L-(+)-diisopropyl tartrate or L-(+)-diethyl
tartrate, and tert-butyl hydroperoxide. Compound (13) is
subsequently converted to compound (20) by the same series of
reactions as described for the conversion of compound (3) to
compound (10) in Scheme 1.
A preferred embodiment of the process of the invention for
preparing cis-substituted chiral 3-aminopyrrolidines is that
wherein, in step (a) the 2-butene-1,4-diol is the cis isomer; in
step (b), the optically active chiral tartrate ester is
D-(-)-diisopropyl tartrate; and the product has the
cis-3S,4S-configuration.
Another preferred embodiment of the process of the invention for
preparing cis-substituted chiral 3-aminopyrrolidines is that
wherein, in step (a) the 2-butene-1,4-diol is the cis isomer; in
step (b), the optically active chiral tartrate ester is
L-(+)-diisopropyl tartrate; and the product has the
cis-3R,4R-configuration.
Still another preferred embodiment of the process of the invention
for preparing trans-substituted chiral 3-aminopyrrolidines is that
wherein in step (a) the 2-butene-1,4-diol is the trans-isomer; in
step (b), the optically active chiral tartrate ester is
D-(-)-diisopropyl tartrate; and the product has the
trans-3R,4S-configuration.
Yet another preferred embodiment of the process of the invention
for preparing trans-substituted chiral 3-aminopyrrolidines is that
wherein in step (a) the 2-butene-1,4-diol is the trans-isomer; in
step (b), the optically active chiral tartrate ester is
L-(+)-diisopropyl tartrate; and the product has the
trans-3S,4R-configuration.
An additional preferred embodiment of the process of the invention
for preparing chiral 3-aminopyrrolidines is that wherein R.sup.1 is
t-butyloxycarbonyl and in step (a) the 2-butene-1,4-diol is treated
with one equivalent of NaH in an aprotic polar organic solvent at
from -20.degree. C. to 5.degree. C. under an inert atmosphere and
anhydrous conditions, and the arylmethyl halide of the subsequent
reaction, performed at ambient temperature for 8 to 24 hours, is
selected from the group consisting of benzyl bromide, benzyl
chloride, benzyl iodide, 4-bromobenzyl bromide, and 4-chlorobenzyl
bromide; in step (b), the first intermediate compound is reacted
with titanium isopropoxide, an optically active chiral tartrate
ester and tert-butyl hydroperoxide in dry methylene chloride in the
presence of 4 .ANG. molecular sieves at -40.degree. C. to
-20.degree. C. for 0.5 to 24 hours; in step (c) the Grignard
reaction is performed with a CuCN catalyst at -78.degree. to
-20.degree. C., followed by treatment of the intermediate with
NaIO.sub.4 at ambient temperature in aqueous THF; in step (d) the
protecting group is removed from the chiral third intermediate
compound by hydrogenolysis over Pd/C in an alcoholic solution; in
step (e) the fourth intermediate compound (5) is sulfonylated with
methanesulfonyl chloride; in step (f) the chiral diprotected triol
compound (6) is cyclized with benzylamine in an alcoholic solution
and in the presence of a base at 80.degree. C.-120.degree. C.; in
step (g) the hydroxyl group of the chiral pyrrolidine intermediate
is replaced by treatment with Ph.sub.3 P, DEAD, and phthalylamine,
followed by treatment with hydrazine in ethanol; in step (h), the
seventh intermediate compound is derivatized by treatment with
di-t-butyldicarbonate; and in step (i), the ring nitrogen of the
chiral substituted-aminopyrrolidine compound is deprotected by
hydrogenolysis over Pd/C in an alcoholic solution.
A more preferred embodiment of the process of the invention for
preparing chiral 3-aminopyrrolidines is that wherein R is
C.sub.1-C.sub.6 -alkyl.
A specifically preferred embodiment of the process of the invention
for preparing chiral 3-aminopyrrolidines is that wherein R is
ethyl.
Another aspect of the invention is a process for preparing specific
chiral cis- or trans-isomers of the
2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane or
2,9-diaza-9-substituted-bicyclo[5.3.0]decane compounds.
Chiral cis-bicyclic compounds may be obtained by the use of the
cis-isomer of 2-butene-1,4-diol in step (a) of the process. The
chiral cis-bicyclic compound having either the 3S,4S- or the
3R,4R-configuration (analogous to the corresponding 3- and
4-positions of the 3-aminopyrrolidine compounds described in
Schemes 1 and 2 above) may be obtained by varying the optically
active tartrate ester referred to in step (b) of the process for
bicyclic compounds described above. Specifically, when the
oxidation is performed with the assistance of the D-(-)-tartrate
ester, the 3S,4S-product is obtained. Conversely, when the
oxidation is performed with the assistance of the L-(+)-tartrate
ester, the 3R,4R-product is obtained.
Chiral trans-bicyclic compounds may be obtained by the use of the
trans-isomer of 2-butene-1,4-diol in step (a) of the process. The
chiral trans-bicyclic compound having either the 3S,4R- or the
3R,4S-configuration (analogous to the corresponding 3- and
4-positions of the 3-aminopyrrolidine compounds described in
Schemes 1 and 2 above) may be obtained by varying the optically
active tartrate ester referred to in step (b) of the trans-process
described above. Specifically, when the oxidation is performed with
the assistance of the L-(+)-tartrate ester, the 3S,4R-product is
obtained. Conversely, when the oxidation is performed with the
assistance of the D-(-)-tartrate ester, the 3R,4S-product is
obtained.
The process of the invention for obtaining specific chiral cis- and
trans-isomers of the desired bicyclic compounds may be better
understood by reference to the reaction Schemes 3 and 4 illustrated
below. ##STR21##
Scheme 3 describes the manner in which the process may be utilized
for preparing the trans-isomers of chiral
2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]decane compounds. Compound
(13) (prepared from trans-2-butene-1,4-diol as shown in Scheme 2)
is reacted with a vinyl, allyl or 3-butenylmagnesium halide,
wherein the halide is bromine, chlorine or iodine, under Grignard
Reaction conditions, as described in Scheme 1 to give compound
(21). The reaction mixture is then preferably treated with
NaIO.sub.4 or KIO.sub.4 to remove 1,2-diol by-products in a polar
organic solvent at ambient temperature. Compound (21) is
subsequently converted to compound (26) by the same series of
reactions as described for the conversion of compound (3) to
compound (9) in Scheme 1.
Compound (26) is then oxidized with a hydroboration reagent, for
example BH.sub.3 in the presence of hydroxide ion and H.sub.2
O.sub.2, to give compound (27).
Compound (27) is treated with a substituted sulfonyl chloride
compound to give compound (28), wherein L represents the
substituted sulfonyl moiety.
Compound (28) is then cyclized to compound (29) by treatment with
NaH under anhydrous conditions in an aprotic solvent.
Alternately, compound (27) may be directly converted into compound
(29) by treatment under Mitsunobu Reaction conditions with Ph.sub.3
P and DEAD in an aprotic solvent.
Compound (29) is then deprotected to give the desired compound
(30). The arylmethyl group may be removed by treatment with sodium
in liquid ammonia or by hydrogenolysis in a polar organic solvent
at ambient temperature, preferably with the aid of a Pd catalyst,
such as Pd/C or palladium acetate. ##STR22##
Scheme 4 describes the manner in which the process may be utilized
for preparing the cis-isomers of chiral
2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]decane compounds. Compound
(3) (prepared from cis-2-butene-1,4-diol as shown in Scheme 1) is
reacted with a vinyl, allyl or 3-butenylmagnesium halide, wherein
the halide may be bromine, chlorine or iodine, under Grignard
Reaction conditions as described in Scheme 1 to give compound (31).
The reaction mixture is then preferably treated with NaIO.sub.4 or
KIO.sub.4 to remove 1,2-diol by-products in a polar organic solvent
at ambient temperature.
Compound (31) is subsequently converted to compound (33) by the
same series of reactions as described for the conversion of
compound (21) to compound (30) in Scheme 3.
One embodiment of the process described in Schemes 3 and 4 is that
in which steps (j) and (k) are combined into one step, in which the
compound having the formula ##STR23## is treated with
triphenylphosphine and diethylazodicarboxylate under Mitsunobu
Reaction conditions, and isolating the chiral bicyclic compound
having the formula: ##STR24##
A preferred embodiment of the process of the invention is that for
preparing cis-isomers of chiral
2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]decane compounds wherein, in
step (a) the 2-butene-1,4-diol is the cis isomer, in step (b), the
optically active chiral tartrate ester is D-(-)-diisopropyl
tartrate, and the product has the S,S-configuration at the chiral
centers.
Another preferred embodiment of the process of the invention is
that for preparing cis-isomers of chiral
2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]-decane compounds wherein, in
step (a) the 2-butene-1,4-diol is the cis-isomer, in step (b), the
optically active chiral tartrate ester is L-(+)-diisopropyl
tartrate, and the product has the R,R-configuration at the chiral
centers.
Stir another preferred embodiment of the process of the invention
is that for preparing trans-isomers of chiral
2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]-decane compounds wherein, in
step (a) the 2-butene-1,4-diol is the trans-isomer, in step (b),
the optically active chiral tartrate ester is D-(-)-diisopropyl
tartrate; and the product has the R,S-configuration at the chiral
centers.
Yet another preferred embodiment of the process of the invention is
that for preparing trans-isomers of chiral
2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]-decane compounds wherein, in
step (a) the 2-butene-1,4-diol is the trans-isomer, in step (b),
the optically active chiral tartrate ester is L-(+)-diisopropyl
tartrate; and the product has the S,R-configuration at the chiral
centers.
An additional preferred embodiment of the process of the invention
for preparing chiral 2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]decane compounds is that
wherein R.sup.1 is t-butyloxycarbonyl and in step (a) the
2-butene-1,4-diol is treated with one equivalent of NaH in an
aprotic polar organic solvent at from -20.degree. C. to 5.degree.
C. under an inert atmosphere and anhydrous conditions, and the
arylmethyl halide of the subsequent reaction, performed at ambient
temperature for 8 to 24 hours, is selected from the group
consisting of benzyl bromide, benzyl chloride, benzyl iodide,
4-bromobenzyl bromide, and 4-chlorobenzyl bromide; in step (b), the
first intermediate compound is reacted with titanium isopropoxide,
an optically active chiral tartrate ester and tert-butyl
hydroperoxide in dry methylene chloride in the presence of 4 .ANG.
molecular sieves at -40.degree. C. to -20.degree. C. for 0.5 to 24
hours; in step (c) the Grignard reaction is performed with a CuCN
catalyst at -78.degree. to -20.degree. C., followed by treatment of
the intermediate with NaIO.sub.4 at ambient temperature in aqueous
THF; in step (d) the protecting group is removed from the chiral
third intermediate compound by treatment with Na and NH.sub.3 ; in
step (e) the fourth intermediate compound (5) is sulfonylated with
methanesulfonyl chloride; in step (f) the chiral diprotected triol
compound (6) is cyclized with benzylamine in an alcoholic solution
and in the presence of a base at 80.degree. C.-120.degree. C.; in
step (g) the hydroxyl group of the chiral pyrrolidine intermediate
is replaced by treatment with Ph.sub.3 P, DEAD, and phthalylamine,
followed by reaction with hydrazine in ethanol; in step (h),
derivatizing the amino group by treatment with
di-t-butyldicarbonate; in step (i) the hydroborating reagent is
BH.sub.3 in the presence of hydroxide ion and H.sub.2 O.sub.2 ; in
step (j) the substituted sulfonyl chloride is methanesulfonyl
chloride; in step (k) cyclizing by treatment with NaH under
anhydrous conditions in an aprotic solvent; and in step (l)
deprotecting the ring nitrogen by hydrogenolysis over Pd/C in an
alcoholic solution.
A more preferred embodiment of the process of the invention for
preparing chiral 2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]decane compounds is that
wherein R.sup.1 is C.sub.1 -C.sub.6 -alkyl.
A specifically preferred embodiment of the process of the invention
for preparing chiral 2,7-diaza-7-substituted-bicyclo[3.3.0]octane,
2,8-diaza-8-substituted-bicyclo[4.3.0]nonane and
2,9-diaza-9-substituted-bicyclo[5.3.0]decane compounds is that
wherein R.sup.1 is hydrogen or methyl.
EXAMPLES
The invention may be better understood by reference to the
following examples, which are provided for the illustration and not
limitation of the invention.
EXAMPLE 1
Reference synthesis of
1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]-nonyl)-7-fluoro-4H-9-methy
l-4-oxo-quinolizine-3-carboxylic acid hydrochloride
Step 1a.
6-(1-(S)-phenylethyl))-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-5,7-dione
A 10 g sample of 2,3-pyridinedicarboxylic anhydride (Aldrich) was
dissolved in 100 mL of anhydrous THF and cooled to 0.degree. C. To
this solution was added 8.70 mL of (S)-(-)-alpha-methylbenzylamine.
The solution was warmed to room temperature and stirred for 30
minutes, then 11.96 g of 1,1'-carbonyldiimidazole was added. The
reaction was stirred at room temperature under N.sub.2 for 20
hours. The solvent was removed, and the residue was dissolved in
methylene chloride. The solvent was washed with water and dried
over MgSO.sub.4. The solvent was removed under vacuum to give
15.344 g of the title compound.
Step 1b.
8-(1-(S)-phenylethyl)-2,8-diazobicyclo[4.3.0]nonan-7,9-dione
A 15.344 g sample of the compound from step 1a above was
hydrogenated over Pd/C in 2-methoxyethanol at 4 atm H.sub.2 and
100.degree. C. for 22 hours. The catalyst and solvent were removed
to give 10.12 g of the title compound. Step 1c.
8-(1-(S)-phenylethyl)-2,8-diazobicyclo[4.3.0]nonane
A 10.12 g sample of the compound from step 1b was dissolved in 30
mL of THF, and this solution was added dropwise to a suspension of
3.13 g of LAH in 50 mL of anhydrous THF stirred at 0.degree. C.
under N.sub.2. After addition was complete, the mixture was heated
at reflux for 9 hours. The reaction was quenched at 0.degree. C. by
sequential addition of 25 mL of H.sub.2 O, 25 mL of 15% KOH and 25
mL of H.sub.2 O. The solids were removed by filtration, and the
filtrate was extracted with ether. The extract was dried over
MgSO.sub.4, and the solvent was removed to give 7.98 g of the title
compound.
Step 1d.
2-BOC-8-(1-(S)-phenylethyl)-2,8-diazobicyclo[4.3.0]nonane
A 7.98 g sample of the compound from step 1c above was dissolved in
75 mL of 2:1 methanol:H.sub.2 O. The solution was cooled to
0.degree. C., and 7.94 g of di-t-butyl dicarbonate was added. The
mixture was then warmed to room temperature and stirred for 1 hour.
The organic solvent was removed under vacuum, and the residue was
slurried with methylene chloride. The organic phase was separated,
washed and dried. The solvent was removed, and the residue was
purified by chromatography on silica gel, eluting with 100:5:0.5
methylene chloride:methanol:ammonium hydroxide, to give 4.6 g of
the title compound as an oil. This material was separated into the
1,6-(R,R)- and 1,6-(S,S)-isomers by HPLC using a chiral support.
The R,R-isomer had an [.alpha.].sub.D of +31.9.degree. C.
(23.degree., c=1.01, methanol); The S,S-isomer had an
[.alpha.].sub.D of -84.6.degree. C. (23.degree. , c=1.04, methanol)
(for additional information on assignment of isomers, refer to
Poster #642, ICAAC 32nd Annual Meeting, 1994).
Step 1e. (S,S)-2-BOC-2,8-diazobicyclo[4.3.0]nonane
A 1.328 g sample of the S,S-isomer from step 1d above and 1.27 g of
ammonium formate were dissolved in 40 mL of methanol. The flask was
flushed with N.sub.2, 130 mg of 10% Pd/C was added, and the
reaction mixture was heated at reflux for 1.5 hours. The solution
was cooled and filtered, then the solvent was removed. The residue
was dissolved in methylene chloride and filtered again. The solvent
was removed under vacuum to give the title compound (858 mg).
[.alpha.].sub.D -70.8.degree. C. (23.degree., c=1.30,
methanol).
Step 1f.
1-cyclopropyl-8-(S,S-2,8-diaza-8-bicyclo[4.3.0]nonyl)-7-fluoro-4H-9-methyl
-4-oxo-quinolizine-3-carboxylic acid hydrochloride
A sample of
1-cyclopropyl-8-chloro-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic
acid ethyl ester was dissolved in anhydrous acetonitrile, and
sodium bicarbonate and
1,6-(S,S)-2-BOC-2,8-diazobicyclo[4.3.0]nonane (from step 1e above)
were added. The mixture was heated at reflux under nitrogen for 7
hours, then the solvent was removed and the residue was redissolved
in methylene chloride. This solution was washed with water, 5% HCl,
water, and concentrated. The residue was purified by flash
chromatography, eluting with 100:10 methylene chloride:methanol,
followed by 100:10:0.5 methylene chloride:methanol:NH.sub.4 OH.
Removal of the solvent gave the free base of the ester of the title
compound. The ester was hydrolyzed by treatment with LiOH.H.sub.2 O
in aqueous THF under nitrogen for 3 hours. The THF was removed
under vacuum, and the residue was adjusted to a pH between 2 and 4
with 1 N HCl. The solid was collected, and the filtrate was
extracted with methylene chloride and washed and concentrated to
give additional product. The combined solids were purified by flash
chromatography eluting with 100:5:1 methylene
chloride:methanol:acetic acid to yield free base of the title
compound. The base was converted to the HCl salt by treatment with
HCl in ether/methylene chloride. The precipitate was collected by
filtration and washed with ether. The solid was dissolved in water,
filtered through a sintered glass funnel, and freeze-dried to give
the title product. mp 230.degree.-232.degree. C. (dec). MS 346
(M--Cl ).sup.+ ; .sup.1 H NMR (DMSO) .delta.: 0.58 (m, 2H), 0.99
(m, 2H), 2.15 (m, 1H), 2.31 (m, 2H), 2.63 (s, 3H), 3.77 (m, 2H),
3.99-4.06 (m, 3H), 7.94 (s, 1H), 8.39 (br s, 3H), 9.10 (d, 1H, J+11
Hz), 13.85 (br s); IR 3440, 1695, 1610 cm.sup.-1.
EXAMPLE 2
Reference synthesis of
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methy
l-4-oxo-quinolizine-3-carboxylic acid hydrochloride diastereomer
A
Step 2a. 2-pentenoic acid ethyl ester
Propionaldehyde (5.8 g) and
(carbethoxymethylene)triphenylphosphorane (35 g) were dissolved in
methylene chloride (100 mL), and the mixture was refluxed
overnight. The product was distilled off from the reaction
mixture.
Step 2b. trans-3-(BOC-amino)-1-CBZ-4-ethyl-pyrrolidine
The compound from step 2a and 5 g of
N-benzyl-N-(methoxymethyl)trimethyl-silylamine were dissolved in 30
mL of dry methylene chloride. The solution was stirred at 0.degree.
C., and 1% trifluoroacetic acid was added dropwise. The mixture was
then stirred for 1.5 hours at room temperature. The solvent was
removed, and the residue was chromatographed on silica gel to give
the title compound.
Step 2c. trans-1-CBZ-3-(BOC-amino)-4-ethylpyrrolidine
The compound from step 2b was dissolved in 20 mL of ethanol, and 10
equivalents of ammonium formate and 170 mg of 10% Pd/C were added.
The reaction mixture was heated at reflux and stirred for 30
minutes. The mixture was filtered, and the filtrate was evaporated.
The residue was dissolved in 10 mL of dioxane and 2.5 mL of water,
and 20% Na.sub.2 CO.sub.3 was added. The mixture was cooled to
0.degree. C., and 1.5 equivalents of benzyloxy-carbonyl chloride
was added slowly. The reaction was stirred for 30 minutes, then
diluted with 100 mL of ether. The organic layer was separated,
washed with brine and dried over MgSO.sub.4. The solvent was
removed, and the residue was chromatographed on silica gel. This
product was dissolved in 12 mL of THF, the solution was cooled to
0.degree. C., and 4 equivalents of LiOH in 3 mL of water were
added. The mixture was stirred at 0.degree. C. for 2 hours, then
diluted with water and acidified with 2 N HCl to pH 2. The mixture
was extracted with ether, and the extract was washed with brine and
dried. The solvent was removed, and the residue was chromatographed
on silica gel to give the intermediate acid. This compound was
dissolved in 10 mL of anhydrous t-butanol, and 1.1 equivalent of
DPPA and 4 equivalents of triethylamine were added. The mixture was
heated at reflux for 24 hours, then cooled. The solvent was
removed, and the residue was chromatographed on silica gel. The
diastereomers were separated by chiral HPLC on a Chiralpak AS.TM.
column, and diastereomer A (chirality not determined) was carried
forward to the next step. .sup.1 H NMR (CDCl.sub.3) .delta.: 7.4
(m, 5H), 5.18 (s, 2H), 6.4-4.60 (m, 3H), 4.30 (m, 1H), 3.60-3.80
(m, 3H), 3.10 (m, 2H), 1.95 (m, 1H), 1.60 (m, 1H), 1.30 (m, 1H),
0.95 (t, 3H), 1.95 (s, 9H). Diastereomer B (chirality not
determined) was carried forward to Example 573.
Step 2d. trans-3-(BOC-amino)-4-ethyl-pyrrolidine
The compound from step 2c was hydrogenated with Pd/C in ethanol,
and the title compound was isolated.
Step 2e.
8-(trans-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methy
l-4-oxo-quinolizine-3-carboxylic acid hydrochloride
A sample of
1-cyclopropyl-8-chloro-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic
acid ethyl ester was dissolved in anhydrous acetonitrile, and
sodium bicarbonate and trans-3-(BOC-amino)-4-ethyl-pyrrolidine
(from step 2d above) were added. The mixture was heated at reflux
under nitrogen for 7 hours, then the solvent was removed and the
residue was redissolved in methylene chloride. This solution was
washed with water, 5% HCl, water, and concentrated. The residue was
purified by flash chromatography, eluting with 100:10 methylene
chloride:methanol. Removal of the solvent gave the free base of the
ester of the title compound. The ester was hydrolyzed by treatment
with LiOH.H.sub.2 O in aqueous THF under nitrogen for 3 hours. The
THF was removed under vacuum, and the residue was adjusted to a pH
between 2 and 4 with 1 N HCl. The solid was collected, and the
filtrate was extracted with methylene chloride and washed and
concentrated to give additional product. The combined solids were
purified by flash chromatography eluting with 100:5:1 methylene
chloride:methanol:acetic acid to yield the free base of the title
compound. The base was converted to the HCl salt by treatment with
HCl in ether/methylene chloride. The precipitate was collected by
filtration and washed with ether. The solid was dissolved in water,
filtered through a sintered glass funnel, and freeze-dried to give
the title product. MS m/z 474 (M+H).sup.+..sup.1 H NMR
(DMSO-d.sub.6) & 9.10 (d, 1H), 8.50 (s, 1H), 4.10 (m, 2H),
3.50-3.80 (m, 3H), 2.60 (s, 3H), 2.30 (m, 2H), 1.7 (m, 1H), 1.40
(m, 1H), 1.0 (m, 5H), 0.6 (m, 2H).
EXAMPLE 3
Reference synthesis of
8-(cis-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro
-4H-9-methyl-4-oxo-quinolizine-3-carboxylic acid hydrochloride
diastereomer A
Step 3a. 1-CBZ-3-pyrroline
3-Pyrroline (Aldrich, 65% purity) was dissolved in a 1:1 mixture of
dioxane and H.sub.2 O.Na.sub.2 CO.sub.3 was added. The reaction
mixture was then flushed with N.sub.2 and cooled to 0.degree. C.
Benzylchloroformate was added dropwise and the mixture was stirred
at 0.degree. C. for several hours. The reaction mixture was allowed
to reach room temperature and was stirred for an additional 2
hours. Ethyl acetate was then added and the reaction mixture was
washed with H.sub.2 O and brine. The organic layer was dried over
MgSO.sub.4, concentrated in vacuo and column chromatographed in a
hexane/EtOAc solution to afford the title compound (65%
purity).
Step 3b. 3,4-epoxy-1-CBZ-pyrroline
Five grams of crude 1-CBZ-3-pyrroline from step 3a was dissolved in
25 mL of CH.sub.2 Cl.sub.2. 3-Chloroperoxybenzoic acid was added
over 5 minutes, and the reaction mixture was allowed to stir at
room temperature for 22 hours. The reaction mixture was then
filtered, and filtrate was diluted with 30 mL of CH.sub.2 Cl.sub.2
and washed with Na.sub.2 S.sub.2 O.sub.3 solution, NaHCO.sub.3
solution and H.sub.2 O. The organic layer was dried over
MgSO.sub.4, concentrated in vacuo, and chromatographed on silica
gel eluting with hexane/EtOAc solution. The title compound was
obtained in 76% yield. MS m/z 220 (M+H).sup.+..sup.1 H NMR
(CDCl.sub.3).delta.: 3.35 (ddd, 2H), 3.65-3.70 (m, 2H), 3.80-3.90
(dd, 2H), 5.15 (d, 2H), 7.30-7.40 (m, 5H).
Step 3c. cis-3-(hydroxy)-1-CBZ-4-ethyl-pyrrolidine
The compound from step 3b (2.0 g) was dissolved in 20 mL of THF,
and CuCN (0.081 g) was added. The mixture was cooled to -70.degree.
C., and 5.5 mL of EtMgCl solution was then added over 20 minutes.
The mixture was allowed to warm to -50.degree. C. and was stirred
at this temperature for 1 hour. The solution was then allowed to
warm to -20.degree. C. over the next hour. Finally, the solution
was left to stir overnight and allowed to reach room temperature.
The following morning, the reaction was quenched with 2N HCl. EtOAc
was added, and the layers were separated. The organic layer was
washed with H.sub.2 O and saturated NaCl solution, dried over
MgSO.sub.4, concentrated in vacuo, and chromatographed on silica
gel to give the title compound in 88% yield. MS m/z 250
(M+H).sup.+..sup.1 H NMR (CDCl.sub.3) .delta.: 0.90-1.00 (t, 3H),
1.15-1.35 (m, 1H), 1.45-1.65 (m, 3H), 1.90-2.05 (m, 1H), 3.10-3.25
(m, 1H), 3.25-3.40 (m, 1H), 3.60-3.75 (m, 2H), 5.14 (s, 2H),
7.25-7.40 (m, 5H). p Step 3d.
cis-3-(phthalimide)-1-CBZ-4-ethyl-pyrrolidine
The compound from step 3c (5.22 g), PPh.sub.3 (8.24 g) and
phthalimide (4.0 g) were placed in a flask, flushed with N.sub.2,
cooled to 0.degree. C., and dissolved in 50 mL of THF. DEAD (4.3
mL) was then added dropwise over 25 minutes. The resultant solution
was stirred for 51 hours at room temperature. The solvent was then
removed in vacuo and the product was purified by column
chromatography to give the title compound in 86% yield. MS m/z 379
(M+H).sup.+..sup.1 H NMR (CDCl.sub.3).delta.:0.85-0.95 (m, 2H),
1.15-1.40 (m, 3H), 2.37-2.53 (m, 1H), 3.42 (t, 1H), 3.75-4.00 (m,
2H), 4.10-4.35 (m, 1H), 7.27-7.45 (m, 5H), 7.72-7.80 (m, 2H),
7.80-7.90 (m, 2H).
Step 3e. cis-3-(BOC-amino)-1-CBZ-4-ethyl-pyrrolidine
The compound from step 3d (6.56 g) was dissolved in EtOH, NH.sub.2
NH.sub.2.H.sub.2 O (2.7 mL) was added and the mixture was refluxed
for 5.5 hours. The reaction mixture was then cooled, filtered, and
the filtrate was concentrated in vacuo. The residue was dissolved
in 20 mL of CH.sub.2 Cl.sub.2 and cooled to 0.degree. C. BOC.sub.2
O (4.9 g), Et.sub.3 N (3.0 mL), and a catalytic amount of DMAP were
added and the mixture was allowed to reach room temperature while
stirring overnight. The following morning CH.sub.2 Cl.sub.2 was
added, and the mixture was washed with NaHCO.sub.3 solution,
H.sub.2 O and brine. The organic layer was dried over MgSO.sub.4,
concentrated in vacuo and column chromatographed in a hexane/EtOAc
solution. The diastereomers were separated by chiral HPLC on a
Chiralpak AS.TM. column. Diastereomer A was carried forward to the
next step. MS m/z 349 (M+H).sup.+..sup.1 H NMR
(CDCl.sub.3).delta.:0.90-1.00 (td, 3H), 1.20-1.50 (m, 2H), 1.45 (s,
9H), 2.05-2.12 (m, 1H), 3.01 (q, 1H), 3.41 (t, 1H), 3.51-3.71 (m,
2H), 4.24 (broad s, 1H), 4.53 (broad s, 1H), 5.13 (s, 2H),
7.18-7.40 (m, 5H). Diastereomer B was carried forward to Example
575.
Step 3f. cis-3-(BOC-amino)-4-ethyl-pyrrolidine
The compound from step 3e was hydrogenated with Pd/C in ethanol as
in Example 2d, and the title compound was isolated. MS m/z 215
(M+H).sup.+..sup.1 H NMR (CDCl.sub.3).delta.: 0.90-1.00 (m, 3H),
1.42 (s, 9H), 2.00-2.10 (m, 2H), 2.50-2.60 (m, 1H), 2.80-2.90 (m,
1H), 3.15-3.25 (m, 2H), 4.12-4.25 (m, 1H), 4.75-4.85 (m, 1H).
Step 3g.
8-(cis-3-amino-4-ethylpyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-4H-9-methyl-
4-oxo-quinolizine-3-carboxylic acid hydrochloride
A sample of
1-cyclopropyl-8-chloro-7-fluoro-4H-9-methyl-4-oxo-quinolizine-3-carboxylic
acid ethyl ester was dissolved in anhydrous acetonitrile, and
sodium bicarbonate and cis-3-(BOC-amino)-4-ethyl-pyrrolidine (from
step 3f above) were added. The mixture was heated at reflux under
nitrogen for 7 hours, then the solvent was removed and the residue
was redissolved in methylene chloride. This solution was washed
sequentially with water, 5% HCl and water again. The organic layer
was concentrated, and the residue was purified by flash
chromatography, eluting with 100:10 methylene chloride:methanol.
Removal of the solvent gave the free base of the ester of the title
compound. The ester was hydrolyzed by treatment with LiOH.H.sub.2 O
in aqueous THF under nitrogen for 3 hours. The THF was removed
under vacuum, and the residue was adjusted to a pH between 2 and 4
with 1 N HCl. The solid was collected, and the filtrate was
extracted with methylene chloride and washed and concentrated to
give additional product. The combined solids were purified by flash
chromatography eluting with 100:5:1 methylene
chloride:methanol:acetic acid to yield the free base of the title
compound. The base was convened to the HCl salt by treatment with
HCl in ether/methylene chloride. The precipitate was collected by
filtration and washed with ether. The solid was dissolved in water,
filtered through a sintered glass funnel, and freeze-dried to give
the title product. MS m/z 374 (M+H).sup.+..sup.1 H NMR
(DMSO-d.sub.6).delta.: 13.80 (broad s, 1H), 9.14 (d, 1H), 8.42 (s,
2H), 7.78 (s, 1H), 4.20-4.30 (m, 1H), 385-3.95 (m, 2H), 3.78 (d,
1H), 3.66 (t, 1H), 2.61 (s, 3H), 2.33-2.5 (m, 1H), 2.20-2.32 (m,
1H), 1.39-1.61(m, 2H), 0.82-1.10 (m, 5H), 0.48-0.53 (m, 2H).
EXAMPLE 4
(3S ,4S )-3-BOC-amino-4-ethyl-pyrrolidine
Step 4a. (Z)-4-[(4-bromobenzyl)oxy]-2-buten-1-ol
To a cold (0.degree. C.) stirred suspension of NaH (4.8 g, 0.12 mol
of a 60% dispersion in oil previously washed with 3.times.70 mL of
dry hexane ) in dry THF (400 mL) under an atmosphere of nitrogen
was added cis-2-butene-1,4-diol (49 mL, 53 g, 0.6 mol) over 10
minutes. The ice bath was removed and the resulting tan solution
was stirred at room temperature for 30 minutes. Tetrabutylammonium
iodide (300 mg) and 4-bromobenzyl bromide (25 g) were then added,
and the resulting reaction mixture was stirred at room temperature
overnight. Water (5 mL) was added, and the THF was removed by
rotary evaporation. The residue was taken up in Et.sub.2 O (250
mL), washed with 5.times.100 mL water and dried (MgSO.sub.4).
Concentration and Kugelrohr distillation afforded the monoprotected
diol as a light yellow oil (22 g, 92%).
Step 4b.
(2R,3S)-3-[[4-bromobenzyl)oxy]methyl]oxirane-2-methanol
To a cold (-25.degree. C.) stirred suspension of powdered 4 .ANG.
molecular sieves (13.5 g) in dry CH.sub.2 Cl.sub.2 (800 mL) under
an atmosphere of nitrogen was added titanium isopropoxide (9.95 g),
D-(-)-diisopropyl tartrate (11.2 g ) and tert-butyl hydroperoxide
(63.6 mL of a 5-6M solution in decane). The slurry was stirred at
-25.degree. C. for 30 minutes. Allylic alcohol (45 g) was then
added as a solution in CH.sub.2 Cl.sub.2 (200 mL), the resulting
mixture was stirred at -25.degree. C. for 2 hours and stored at
-20.degree. C. freezer for 2 days, and 2 mL of Me.sub.2 S and 200
mL of a 10% aqueous tartaric acid solution were added. The solution
was stirred for 30 minutes, then allowed to warm to room
temperature. It was stirred for an additional 2 hours at room
temperature, and the organic layer was separated, washed with water
and brine, and dried over MgSO.sub.4. The solvent was removed, and
the residue was dissolved in 300 mL of ether and 200 mL of pentane.
The solution was slowly cooled to -20.degree. C. and left
overnight. The white needles were collected by filtration, washed
with pentane and dried in vacuo to afford the title compound (30
g).
Step 4c. (2S,3R)-2-ethyl-4-bromobenzyloxy-1-butan-1,3-diol
To a stirred suspension of CuCN (2.68 g, 30 mmol) in 1000 mL dry
Et.sub.2 O under nitrogen at -50.degree. C. was added 300 mL of
ethyl magnesium bromide (2.0M in ether). The resulting suspension
was stirred for 30 minutes, then 27.3 g of the epoxy alcohol from
step 4b in 150 mL THF was added slowly via cannula. The reaction
mixture was stirred at -50.degree. C. for 5 hours and at
-30.degree. C. for an additional 2 hours. The temperature was then
allowed to reach 0.degree. C. over 2 hours. Aqueous solutions of
NH.sub.4 OH and NH.sub.4 Cl were added, and the mixture was
extracted with ether. The organic extract was washed with saturated
NaCl, dried over MgSO.sub.4, and filtered, and the solvent was
evaporated to afford 31.2 g of a heavy oil. The oil was dissolved
in 300 mL of a 2:1 mixture of THF--H.sub.2 O. NaIO.sub.4 (14.2 g)
was added to the solution, and the mixture was stirred at room
temperature for 4 hours. The THF was removed by rotary evaporation.
Ethyl acetate and brine were then added, the layers were separated,
and the organic layer was dried over MgSO.sub.4, filtered,
concentrated, and column chromatographed to afford 20.93 g of the
title compound.
Step 4d. (2R,3S)-2-ethylbutan-1,3,4-triol
The compound prepared from step 4c was subjected to hydrogenation
under 1 atm of H.sub.2 for 24 hours at room temperature in 500 mL
of EtOH containing 2 eq NaHCO.sub.3 and 10% Pd/C as catalyst. After
filtration, the solvent was removed, and the residue was taken up
in ethyl acetate and methylene chloride (1:1) solution. The
solution was filtered, and the filtrate was evaporated to afford
the desired product (86% yield).
Step 4e. (3R,4S)-1-benzyl-4-ethyl-pyrrolidin-3-ol
To a solution of 4.6 g of the product from step 4d in 60 mL
pyridine cooled to -40.degree. C., MsCl (7.85 g) was added slowly
via syringe. The mixture was stirred for 4 hours at -40.degree. C.
Water (10 mL) was added, and the reaction mixture was allowed to
warm to room temperature. The solvent was removed, and the residue
was taken up in ethyl acetate. The solvent was washed with water, 2
M HCl, NaHCO.sub.3 and brine, and dried over MgSO.sub.4. The
solution was filtered and concentrated to afford the desired
dimesylate compound (85% yield). The dimesylate compound (16.27 g)
was dissolved in 300 mL of absolute EtOH, and 28.22 g NaHCO.sub.3
and 7.21 g of benzyl amine were added. The mixture was heated to
reflux under N.sub.2 for 16 hours, then allowed to cool to room
temperature. The solvent was removed under vacuum, 500 mL ethyl
acetate and 200 mL water were added, and the layers were separated.
The organic layer was washed with brine, dried over MgSO.sub.4,
filtered, and concentrated to afford 10.6 g of the desired
product.
Step 4f. (3S,4S)-1-benzyl-3-BOC-amino-4-ethyl-pyrrolidine
To a solution of 4.24 g of the compound from step 4e in 50 mL THF
were added 5.90 g triphenyl phosphine and 3.31 g phthalimide, then
DEAD (3.91 g) was added via syringe. The resulting solution was
stirred for 1 hour at room temperature then concentrated to
dryness. The residue was dissolved in 50 mL of absolute ethanol,
1.22 g hydrazine monohydrate was added, and the mixture was
refluxed under N.sub.2 for 4 hours. After cooling to room
temperature, concentrated HCl (5.5 mL) was added, the solid was
filtered, and filtrate was concentrated. Water and CH.sub.2
Cl.sub.2 (100 mL of each) were added to the residue. The water
layer was separated and extracted twice with CH.sub.2 Cl.sub.2,
then basified with 20% NaOH. The aqueous solution was extracted
with CH.sub.2 Cl.sub.2. The organic layer was concentrated and
redissolved in 50 mL of a 1:1 mixture of methanol-water, then 4.91
g of di-t-butyl dicarbonate was added. After stirring overnight,
the mixture was concentrated and the product was purified on a
silica gel column to afford 3.72 g of the desired product as a
white solid. 1H NMR (CDCl.sub.3), .delta. 0.85 (t, 3H), 1.20 (m,
1H), 1.40 (s, 10H), 2.20 (m, 1H), 2.30 (m, 1H), 2.45 (m, 1H), 2.65
(t, 1H), 2.80 (m, 1H), 3.60 (q, 2H), 4.20 (m, 1H), 4.80 (m, 1H),
7.30 (s, 5H).
Step 4g. (3S,4S)-3-BOC-amino-4-ethyl-pyrrolidine
A sample of the compound from step 4f is dissolved in ethanol and
treated with 4 atm of H.sub.2 over Pd/C for 24 hours. The
deprotected compound is not stored, but is taken directly to the
condensation step illustrated in, for example, Example 3, step
f.
EXAMPLE 5
(3S,4R-)-3-BOC-amino-4-ethyl-pyrrolidine
Step 5a. E-2-butene-1,4-diol
LAH (25 g) was added to dry Et.sub.2 O (1L) under a good nitrogen
flow, and the mixture was cooled to -10.degree. C.
2-butyne-1,4-diol (35 g dissolved in 200 mL of dry THF) was added
dropwise while the reaction temperature was maintained at
-10.degree. C. Upon completion of the addition, the temperature was
allowed to warm to 0.degree. C. The reaction mixture was then
heated to reflux for 15 hours. The mixture was cooled to
-10.degree. to 0.degree. C. and 25 mL of water were added dropwise
while the mixture was vigorously stirred. 25 mL of a 15% NaOH
solution were then added dropwise with continued stirring, followed
by an additional 75 mL of H.sub.2 O. The resulting white solid was
removed by filtration and washed with 1L of DME. The filtrate,
including the DME wash solution, was concentrated in vacuo to
afford 31 g of the title product.
Step 5b. E-4-Benzyloxy-2-butene-1-ol
NaH (11.5 g of a 60% dispersion in mineral oil) was placed in a 2L,
3-neck flask equipped with a dropping funnel and nitrogen inlet.
The NaH was rinsed with hexane (3.times.30 mL), and 1L of dry THF
was added with a good nitrogen flow. The mixture was then cooled to
-10.degree. C. E-1,4-hydroxy-2-butene (32.94 g, 0.379 mol) was
dissolved in 200 mL of dry THF. The THF mixture was added dropwise
while maintaining the reaction temperature at -10.degree. C. The
reaction was allowed to reach room temperature while being stirred
for 1 hour, Bu.sub.4 NI (1.0 g) was added, then BnBr (34.2 mL,
0.288 mol) was added via syringe over 5 minutes. The mixture was
refluxed for 12 hours, then allowed to cool to room temperature.
THF was removed by rotary evaporation, and 500 mL of Et.sub.2 O and
100 mL of H.sub.2 O were added. The layers were separated. The
organic layer was then washed with water (1.times.50 mL) and brine
(1.times.50 mL), dried over MgSO.sub.4, filtered, concentrated and
column chromatographed to afford 20.3 g the title compound. MS 196
(M+NH.sub.4).sup.+. .sup.1 H NMR .delta. 4.03-4.07 (m, 2H),
4.15-4.21 (m, 2H), 4.53 (s, 2H), 5.80-5.99 (m, 2H), 7.25-7.38 (m,
5H).
Step 5c. (2S,3S)-[(benzyloxymethyl]oxirane-2-methanol
L-(+)-Diethyl tartrate dissolved in 25 mL of dry CH.sub.2 Cl.sub.2
was slowly added to a stirred solution of titanium isopropoxide in
800 mL of dry CH.sub.2 Cl.sub.2 at -23.degree. C. under a nitrogen
atmosphere. The mixture was stirred for 15 minutes.
E-1-Benzyloxy-4-hydroxy-2-butene (17.8 g dissolved in 100 mL of dry
CH.sub.2 Cl.sub.2) was added dropwise through a dropping funnel.
t-BuOOH (41.2 mL of a 5.0-6.0M solution in decane) was then added
at about -23.degree. to -30.degree. C., and the mixture was stored
overnight at -25.degree. C. The reaction mixture was stirred for
7.5 hours at -23.degree. to -30.degree. C., and Me.sub.2 S (2 mL)
and 10% aqueous tartaric acid solution (100 mL) were added. The
mixture was stirred for 30 minutes, then allowed to reach room
temperature and stirred for an additional 1.5 hours. The mixture
was poured into a separatory funnel, and the layers were separated.
The organic layer was washed with H.sub.2 O (2.times.100 mL) and
brine (1.times.100 mL). The combined aqueous layers were then
extracted with CH.sub.2 Cl.sub.2. The combined organic layers were
then dried over MgSO.sub.4, concentrated by rotary evaporation, and
column chromatographed to afford the title compound in 83% yield
(16.1 g). MS 212 (M+NH.sub.4).sup.+..sup.1 H NMR .delta. 1.61 (dd,
1H), 3.12 (ddd, 1H), 3.25 (ddd, 1H), 3.54 (dd, 1H), 3.66 (ddd, 1H),
3.78 (dd, 1H), 3.95 (ddd, 1H), 4.58 (AB q, 2H), 7.26-7.40 (m,
5H).
Step 5d. (2R,3R)-2-ethyl-4-benzyloxybutan-,1,3-diol
3.77 g of CuCN and 1.2L of dry Et.sub.2 O were placed in an
oven-dried flask under a steady flow of nitrogen. The mixture was
cooled to -50.degree. C. 377 mL of 1.0 M EtMgBr in THF was add via
cannula. The reaction mixture was stirred for 15 minutes to allow
the reaction temperature to again reach -50.degree. C.
(2S,3R)-3-[[(benzyloxy]oxirane-2-methanol (24.4 g) dissolved in 400
mL of dry Et.sub.2 O was added via syringe at a rate which allowed
the reaction mixture to be maintained below -50.degree. C. The
reaction mixture was stirred for 2 hours while the temperature was
maintained between -54.degree. and -49.degree. C. Over the next
hour the reaction temperature was maintained at approximately
-40.degree. C. Following that, the temperature was maintained at
about -30.degree. C. for one hour. During the next 4 hours the
temperature was maintained between -36.degree. and -25.degree. C.
After this, the temperature was allowed to reach 0.degree. C. over
the next 2 hours. Aqueous solutions of NH.sub.4 OH and NH.sub.4 Cl
were added to quench the reaction. The solution was poured into a
separatory funnel and the layers separated. The organic layer was
washed with H.sub.2 O and brine. The original aqueous layer was
then extracted with EtOAc. The EtOAc layer was washed with H.sub.2
O and brine and was then combined with the earlier organic layer.
The combined organic layers were then dried over MgSO.sub.4,
filtered and concentrated to afford 24.14 g of a mixture of the
desired compound, the starting material and the 3-position
ring-opened product. MS 242 (M+NH.sub.4).sup.+..sup.1 H NMR .delta.
0.93 (t, 3H), 1.33-1.48 (m, 3H), 2.78 (d, 1H), 2.86 (t, 1H),
3.47-3.95 (m, 5H), 4.58 (s, 2H), 7.27-7.42 (m, 5H).
This mixture was dissolved in 300 mL of a 2:1 mixture of
THF/H.sub.2 O. The reaction flask was placed in a water bath at
room temperature to maintain the reaction temperature during the
addition of 6.02 g of NaIO.sub.4 over a 5 minute period. After
stirring for 45 minutes, the water bath was removed and the
reaction was stirred overnight. The THF was then removed by rotary
evaporation. EtOAc and brine were then added, and the layers were
separated. The combined aqueous layers were extracted with EtOAc.
The combined organic layers were then dried over MgSO.sub.4,
filtered, concentrated, and column chromatographed to afford 14.56
g of the title compound.
Step 5e. (2R,3R)-2-ethylbutan-1,3,4-triol
Hydrogenation of (2S,3S)-2-ethyl-3-hydroxy-4-benzyloxy-1-butanol
(14.56 g, from step 5d) in 500 mL of EtOH was carried out under 4
atm of H.sub.2 for 24 hours at room temperature with 10% Pd/C (7.25
g) catalyst. The catalyst was removed by filtration, and the
solvent was removed by rotary evaporation to afford 8.55 g (94%) of
the title compound.
Step 5f. (3S,4R)-1-benzyl-4-ethyl-pyrrolidin-3-ol
The compound from step 5e (8.55 g) was dissolved in 50 mL of
pyridine. The flask was flushed with nitrogen, maintained under a
nitrogen atmosphere and cooled to -40.degree. to -45.degree. C.,
then methanesulfonyl chloride (9.4 mL) of was added via syringe.
The reaction mixture was stirred for 5 hours between -40.degree.
and -45.degree. C. H.sub.2 O (5 mL) was added, and the mixture was
stirred for 15 minutes, then the reaction mixture was allowed to
warm to room temperature. Pyridine and H.sub.2 O were then removed
by rotary evaporation, EtOAc (500 mL) and H.sub.2 O (20 mL) were
added and the layers were separated. The organic layer was washed
with 2M HCl (4.times.40 mL), dried over MgSO.sub.4, filtered and
concentrated to afford 16.3 g of a mixture of the desired
dimesylate compound and a trimesylate byproduct.
This mixture was dissolved in 200 mL of anhydrous ethanol, and
NaHCO.sub.3 (28.33 g) and BnNH.sub.2 (6.75 mL) were added under
nitrogen. The mixture was heated to reflux, stirred for 19 hours,
then cooled to room temperature and concentrated. EtOAc (500 mL)
and H.sub.2 O (400 mL) were then added, and the layers were
separated. The organic layer was washed with a saturated solution
of Na.sub.2 CO.sub.3, water and brine. The original aqueous layer
was extracted with EtOAc. This EtOAc layer was then washed with a
saturated solution of Na.sub.2 CO.sub.3, water and brine. The
combined organic layers were dried over MgSO.sub.4, filtered and
concentrated to afford 12.02 g of the crude desired product..sup.1
H NMR .delta. 0.93 (t, 3H), 1.30-1.47 (m, 1H), 1.50-1.65 (m, 2H),
1.73 (d, 1H), 1.96-2.11 (m, 1H), 2.23 (t, 1H), 2.62-2.72 (m, 1H),
2.83 (dd, 1H), 3.67 (AB q, 2H), 4.14-4.23 (m, 1H), 7.21-7.27 (m,
3H), 7.32 (d, 2H).
Step 5g. (3S,4R)-1-benzyl-3-BOC-amino-4-ethyl-pyrrolidine
The compound from step 5f is treated according to the procedure of
Example 4, step 5, under Mitsunobu Reaction conditions to afford
the title compound.
Step 5h. (3S,4R)-3-BOC-amino-4-ethyl-pyrrolidine
A sample of the compound from step 5 g is dissolved in ethanol and
treated with 4 atm of H.sub.2 over Pd/C for 24 hours. The
deprotected compound is not stored, but is taken directly to the
condensation step illustrated in, for example, Example 3, step
f.
EXAMPLE 6
(3R,4R)-3-BOC-amino-4-methyl-pyrrolidine
Following the procedures of Example 4, except replacing the
D-(-)-diisopropyl tartrate of step 4b with L-(+)-diisopropyl
tartrate and the ethyl magnesium bromide of step 4c with methyl
magnesium bromide, the title compound is prepared.
EXAMPLE 7
(3R,4S)-3-BOC-amino-4-butyl-pyrrolidine
Following the procedures of Example 5, except replacing the
L-(+)-diethyl tartrate of step 5c with D-(-)-diethyl tartrate and
the ethyl magnesium bromide of step 5d with n-butyl magnesium
bromide, the title compound is prepared.
EXAMPLE 8
(3S,4S)-3-trifluoroacetylamino-4-methyl-pyrrolidine
Following the procedures of Example 4, except replacing the
di-t-butyl dicarbonate of step 4f with trifluoroacetyl anhydride,
the title compound is prepared.
EXAMPLE 9
(3S,4S)-3-methylamino-4-methyl-pyrrolidine
Following the procedures of Example 4, except replacing the
di-t-butyl dicarbonate of step 4f with methyl iodide, the title
compound is prepared.
EXAMPLE 10
(3S ,4S)-3-hexylamino-4-methyl-pyrrolidine
Following the procedures of Example 4, except replacing the
di-t-butyl dicarbonate of step 4f with hexanal in the presence of
K.sub.2 CO.sub.3 followed by reduction with of the imine with
NaCNBH.sub.3, the title compound is prepared.
EXAMPLE 11
(3S ,4S)-3-BOC-amino-4-methyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with methyl magnesium iodide, the
title compound is prepared.
EXAMPLE 12
(3S ,4S)-3-BOC-amino-4-propyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with propyl magnesium iodide, the
title compound is prepared.
EXAMPLE 13
(3S,4S)-3-BOC-amino-4-hexyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with n-hexyl magnesium bromide, the
title compound is prepared.
EXAMPLE 14
(3S,4S)-3-BOC-amino-4-vinyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with vinyl magnesium chloride, the
title compound is prepared.
EXAMPLE 15
(3S ,4S)-3-BOC-amino-4-(2-hexenyl)-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with hex-2-en-1-yl magnesium bromide,
the title compound is prepared.
EXAMPLE 16
(3S,4S)-3-BOC-amino-4-ethynyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with ethynyl magnesium bromide, the
title compound is prepared.
EXAMPLE 17
(3S,4S)-3-BOC-amino-4-(but-2-yn-1-yl)-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with but-2-yn-1-yl magnesium bromide,
the title compound is prepared.
EXAMPLE 18
(3S,4S)-3-BOC-amino-4-cyclopropyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with cyclopropyl magnesium bromide,
the title compound is prepared.
EXAMPLE 19
(3S,4S)-3-BOC-amino-4-cyclobutyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with cyclobutyl magnesium bromide, the
title compound is prepared.
EXAMPLE 20
(3S ,4S)-3-BOC-amino-4-cyclopentyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with cyclopentyl magnesium bromide,
the title compound is prepared.
EXAMPLE 21
(3S ,4S )-3-BOC-amino-4-cyclohexyl-pyrrolidine
Following the procedures of Example 4, except replacing the ethyl
magnesium bromide of step 4c with cyclohexyl magnesium bromide, the
title compound is prepared.
EXAMPLE 22
Preparation of cis-2,8-diaza-8-BOC-bicyclo[4.3.0]nonane
Step 22a.
(2S,3R)-1-bromobenzyloxy-3-hydroxymethyl-hex-5-en-2-ol
To a stirred suspension of CuCN in dry Et.sub.2 O under nitrogen at
-50.degree. C. is added allyl magnesium bromide. The resulting
suspension is stirred for 30 minutes, then
(2R,3S)-3[[-bromobenzyl)oxy]methyl]oxirane-2-methanol (from Example
4, step b) is slowly added. The reaction is stirred at -30.degree.
C. and then 0.degree. C. until the reaction is complete. Aqueous
solutions of NH.sub.4 OH and NH.sub.4 Cl are added, and the mixture
is extracted with ether. The organic extract is washed with
saturated NaCl, dried over MgSO.sub.4, and filtered, and the
solvent is evaporated to afford the desired intermediate. The
intermediate is dissolved in THF--H.sub.2 O and NaIO.sub.4 is added
to the solution, and the mixture is stirred at room temperature for
4 hours. The THF is removed by rotary evaporation. Ethyl acetate
and brine are then added, the layers are separated, and the organic
layer is dried over MgSO.sub.4, filtered, concentrated, and column
chromatographed to afford the title compound.
Step 22b. (2R,3S)-3-hydroxymethyl-hex-5-en-1,2-diol
The compound prepared from step 22a is deprotected with
sodium/ammonia to afford the desired product.
Step 22c.
(2R,3S)-1-methanesulfonyloxy-3-(methanesulfonyloxy)methyl-hex-5-en-2-ol
To a solution of the product from step 22b in pyridine cooled to
-40.degree. C. is added MsCl slowly via syringe. The mixture is
stirred for 4 hours at -40.degree. C., then is quenched with water
and allowed to warm to room temperature. The solvent is removed,
the residue is taken up in ethyl acetate, the solution is washed
with water, 2M HCl, NaHCO.sub.3 and brine, then is dried over
MgSO.sub.4. The solution is filtered and concentrated to afford the
desired dimesylate compound.
Step 22d. (3R,4S)-4-allyl-1-benzylpyrrolidin-3-ol
The dimesylate compound from step 22c is dissolved in absolute EtOH
and treated with benzyl amine at reflux in the presence of
NaHCO.sub.3 under N.sub.2. After cooling, the solvent is removed
under vacuum, and the residue is redissolved, washed and dried. The
solvent is removed to give the title compound.
Step 22e. (3S,4S)-4-allyl-1-benzyl-pyrrolidin-3-amine
The compound from step 22d is treated under Mitsunobu Reaction
conditions with Ph.sub.3 P, DEAD, and phthalylamine, followed by
treatment with hydrazine. The title compound is obtained by
extraction from the reaction mixture.
Step 22f (3S ,4S)-4-allyl-1-benzyl-3-BOC-aminopyrrolidine
The compound from step 22e is treated with di-t-butyl dicarbonate
in methylene chloride. The title compound is obtained by extraction
from the reaction mixture.
Step 22g.
(3S,4S)-4-(3-hydroxypropyl)-1-benzyl-3-BOC-aminopyrrolidine
The compound from step 22f is treated with BH.sub.3 and H.sub.2
O.sub.2 in aqueous NaOH. The title compound is obtained by
extraction from the reaction mixture.
Step 22h.
(3S,4S)-4-(3-methanesulfonyl-oxypropyl)-1-benzyl-3-BOC-aminopyrrolidine
The compound from step 22g is treated with methanesulfonyl chloride
in methylene chloride. The title compound is obtained by extraction
from the reaction mixture.
Step 22i. .cent.cis-2,8-diaza-2-benzyl-bicyclo[4.3.0]nonane
The compound from step 22e is treated with NaH under anhydrous
conditions in THF. The title compound is obtained by extraction
from the reaction mixture.
Step 22j. cis-2,8-diaza-2-benzyl-8-BOC-bicyclo[4.3.0]nonane
The compound from step 22f is treated with di-t-butyl dicarbonate,
and the title compound is obtained by extraction from the reaction
mixture.
Step 22k. cis-2,8-diaza-8-BOC-bicyclo[4.3.0]nonane
The compound from step 22g is treated with H.sub.2 over Pd/C in
ethanol, and the title compound is obtained by extraction from the
reaction mixture.
EXAMPLE 23
Preparation of trans-2,8-diaza-8-BOC-8-bicyclo[4.3.0]nonane
Step 23a.
(2R,3R)-1-bromobenzyloxy-3-hydroxymethyl-hex-5-en-2-ol
To a stirred suspension of CuCN in dry Et.sub.2 O under nitrogen at
-50.degree. C. is added allyl magnesium bromide. The resulting
suspension is stirred for 30 minutes, then
(2S,3S)-3-[[4-bromobenzyl)oxy]methyl]oxirane-2-methanol (from
Example 5, step b) is slowly added. The reaction is stirred at
-30.degree. C. and then 0.degree. C. until the reaction is
complete. Aqueous solutions of NH.sub.4 OH and NH.sub.4 Cl are
added, and the mixture is extracted with ether. The organic extract
is washed with saturated NaCl, dried over MgSO.sub.4, and filtered,
and the solvent is evaporated to afford the desired intermediate.
The intermediate is dissolved in THF--H.sub.2 O and NaIO.sub.4 is
added to the solution, and the mixture is stirred at room
temperature for 4 hours. The THF is removed by rotary evaporation.
Ethyl acetate and brine are then added, the layers are separated,
and the organic layer is dried over MgSO.sub.4, filtered,
concentrated, and column chromatographed to afford the title
compound.
Step23b. (2R,3R)-3-hydroxymethyl-hex-5-en-1,2-diol
The compound prepared from step 23a is deprotected with
sodium/ammonia to afford the desired product.
Step 23c.
(2R,3R)-1-methanesulfonyloxy-3-(methanesulfonyloxy)methyl-hex-5-en-2-ol
To a solution of the product from step 23b in pyridine cooled to
-40.degree. C. is added MsCl slowly via syringe. The mixture is
stirred for 4 hours at -40.degree. C., then is quenched with water
and allowed to warm to room temperature. The solvent is removed,
the residue is taken up in ethyl acetate, the solution is washed
with water, 2M HCl, NaHCO.sub.3 and brine, then is dried over
MgSO.sub.4. The solution is filtered and concentrated to afford the
desired dimesylate compound.
Step 23d. (3R,4R)-4-allyl-1-benzylpyrrolidin-3-ol
The dimesylate compound from step 23c is dissolved in absolute EtOH
and treated with benzyl amine at reflux in the presence of
NaHCO.sub.3 under N.sub.2. After cooling, the solvent is removed
under vacuum, and the residue is redissolved, washed and dried. The
solvent is removed to give the title compound.
Step 23e. (3S,4R)-4-allyl-1-benzyl-pyrrolidin-3-amine
The compound from step 23d is treated under Mitsunobu Reaction
conditions with Ph.sub.3 P, DEAD, and phthalylamine, followed by
treatment with hydrazine. The title compound is obtained by
extraction from the reaction mixture.
Step 23f. (3S,4R)-4-allyl -1-benzyl-3-BOC-aminopyrrolidine
The compound from step 23e is treated with di-t-butyl dicarbonate
in methylene chloride. The title compound is obtained by extraction
from the reaction mixture.
Step 23 g.
(3S,4R)-4-(3-hydroxypropyl)-1-benzyl-3-BOC-aminopyrrolidine
The compound from step 23f is treated with BH.sub.3 and H.sub.2
O.sub.2 in aqueous NaOH. The title compound is obtained by
extraction from the reaction mixture.
Step 23h.
(3S,4R)-(3-methanesulfonyloxypropyl)-1-benzyl-3-BOC-aminopyrrolidine
The compound from step 23g is treated with methanesulfonyl chloride
in methylene chloride. The title compound is obtained by extraction
from the reaction mixture.
Step 23i. trans-2,8-diaza-2-benzyl-8-bicyclo[4.3.0]nonane
The compound from step 23e is treated with NaH under anhydrous
conditions in THF. The title compound is obtained by extraction
from the reaction mixture.
Step 23j. trans-2,8-diaza-2-benzyl-8-BOC-8-bicyclo[4.3.0]nonane
The compound from step 23f is treated with di-t-butyl dicarbonate,
and the title compound is obtained by extraction from the reaction
mixture.
Step 23k. trans-2,8-diaza-8-BOC-bicyclo[4.3.0]nonane
The compound from step 23g is treated with H.sub.2 over Pd/C in
ethanol, and the title compound is obtained by extraction from the
reaction mixture.
EXAMPLE 24
Preparation of cis-2,7-diaza-7-BOC-bicyclo[3.3.0]octane
Following the procedures of Example 22, except replacing the allyl
magnesium bromide of step 22a with vinyl magnesium bromide, and
carrying the product forward, the title compound is prepared.
EXAMPLE 25
Preparation of cis-2,9-diaza-9-BOC-bicyclo[5.3.0]decane
Following the procedures of Example 22, except replacing the allyl
magnesium bromide of step 22a with hex-1-en-4-yl magnesium bromide,
and carrying the product forward, the title compound is
prepared.
EXAMPLE 26
In Vitro Assay of Antibacterial Activity
The in vitro antibacterial activity of the illustrative compounds
was demonstrated as follows: Minimum inhibitory concentrations
(MICs) were determined by the agar dilution method, in which twelve
petri dishes were prepared, each containing successive aqueous
2-fold dilutions of the test compounds mixed with 10 mL of
sterilized Brain Heart Infusion (BHI) agar. Each plate was
inoculated with 1:100 (or 1:10 for slow-growing strains, primarily
Micrococcus and Streptococcus) dilutions of up to 32 different
microorganisms, using a Steers replicator block calibrated to
deliver approximately 104 colony forming units (CFUs). The
inoculated plates were incubated at from about 35.degree. C. to
about 37.degree. C. for approximately 20-24 hours. In addition, a
control plate using BHI agar containing no test compound was
prepared and incubated at the beginning and at the end of each
test. The quinolone antibacterial ciprofloxacin was used as a
control ("Cntl").
After incubation, each petri dish was observed for the presence or
absence of microorganism growth. The MIC was defined as the lowest
concentration of test compound yielding no growth (a slight haze or
sparsely isolated colonies at the inoculum spot) as compared to the
growth control containing no test compound.
The results of the above tests, shown in Table 1 below, demonstrate
that the illustrative compounds are surprisingly effective in
combating bacterial growth.
TABLE 1 ______________________________________ In Vitro
Antibacterial Activity (MIC Values in .mu.g/mL) Organism Ex. 1 Ex.
2 Ex. 3 Control ______________________________________ Staph.
aureus ATCC 6538P 0.01 0.02 0.01 0.05 Staph. aureus A5177 0.02 0.02
0.02 0.39 Staph. aureus 5278 0.01 0.05 0.02 0.39 Staph. aureus 642A
0.02 0.02 0.02 0.39 Staph. aureus NCTC10649M 0.01 -- 0.01 0.39
Staph. aureus CMX 553 0.05 0.02 0.02 0.78 Staph. aureus 1775 Cipro.
R. 0.39 0.78 0.78 >100 Staph. epidermidis 3519 0.02 0.05 0.02
0.39 Entero. faecium ATCC 8043 0.1 0.05 0.1 0.78 Strep. bovis A5169
0.05 0.1 0.1 1.56 Strep. agalactiae CMX 508 0.05 0.02 0.1 0.78
Strep. pyogenes EES61 0.05 0.02 0.1 0.39 Strep. pyogenes 930 CONST
0.05 0.05 0.05 0.78 Strep. pyogenes 2548 INDUC 0.02 0.05 0.05 0.39
M. luteus ATCC 9341 0.1 0.05 0.1 3.1 M. luteus ATCC 4698 0.1 0.05
0.1 1.56 Escherichia coli Juhl 0.005 0.01 0.02 0.05 E. coli SS
0.002 0.001 0.002 0.005 E. coli DC-2 0.05 0.1 0.2 0.2 E. coli H560
0.005 0.01 0.01 0.01 E. coli KNK 437 0.05 0.1 0.1 0.2 Enter.
aerogenes ATCC 13048 0.02 0.1 0.05 0.05 Klebs. pneumoniae ATCC8045
0.01 0.05 0.02 0.01 Providencia stuartii CMX 640 0.39 0.39 0.78
0.78 P. aeruginosa BMH 10 0.1 0.2 0.39 0.1 P. aeruginosa A5007 0.2
0.39 0.39 0.2 P. aeruginosa K799/WT 0.2 0.78 0.39 0.1 P. aeruginosa
K799/61 0.02 0.1 0.02 0.02 Pseudomonas cepacia 296I 0.78 1.56 0.78
3.1 Acinetob. calcoaceticus CMX 669 0.02 0.05 0.02 0.39 P.
aeruginosa 5263 3.1 3.1 3.1 12.5 P. aeruginosa 2862 3.1 6.2 3.1
12.5 Candida albicans CCH 442 >100 >100 >100 >100 Myco.
smegmatis ATCC 114 0.02 0.02 0.02 1.56 Nocardia asteroides ATCC
9970 3.1 0.78 0.39 25 ______________________________________
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